Stabilization of molded sublingual nitroglycerin tablets

ABSTRACT

Methods for preparing nitroglycerin containing pharmaceutical compositions in the form of tablets suitable for sublingual administration, are disclosed, which comprises wetting a substantially dry mixture of the nitroglycerin and a solid, water-soluble pharmaceutical carrier with a solvent mixture containing a non-volatile, water-soluble solvent and a volatile solvent, forming the wetted mixture into tablets, and removing the volatile solvent.

Elite States Patent 11 1 Fusari et a1.

[ 1 Mar. 25, 1975 1 STABILIZATION OF MOLDED SUBLINGL'AL NITROGLYCERIN TABLETS [75] Inventors: Salvatore A. Fusari, St. Clair Shores; Leslie M. Lueck, Oxford.

22] Filed:

I Appl. No.:413,9l5

Related U.S. Application Data [63] Continuation-impart of Ser. No. 149,072, June 1,

1971. Pat. No. 3,787,119.

[52] U.S. Cl 424/366, 149/101, 260/467, 264/3, 424/78, 424/298 Int. Cl A6lk 27/12 Field of Search 264/3; 149/101; 260/467; 424/78, 298, 366

156] References Cited UNITED STATES PATENTS 1.541.744 6/1925 Wiseman 424/361 2,540,253 2/1951 Gakenheimer 424/78 2.698.822 l/1955 Halpern et a1. 424/78 3,648,698 8/1953 Preckel 149/101 3.789119 l/l974 Fusari et al. 424/78 FOREIGN PATENTS OR APPLlCATlONS 1090184 1 H1967 Great Britain 1.226.322 12/1972 Germany 1,409,082 8/1965 France 1.209.034 1/1966 Germany OTHER PUBLICATIONS Stephenson et al., J. Pharm. Pharmacol. 3: 767-776 (1951 Tablets of Glyceryl Trinitrate.

Edelman et al.,J.A.Ph.A. N.S.1 1(1): 30-3, Jan. 1971, The Stability of Hypodermic Tablets of Nitroglycerin Packaged in Dispensing Containers.

Shangraw et al., J.A.Ph.A. No. 12(12): 633-636, Dec., 1972, New Developments in the Manufacture and Packaging of Nitroglycerin Tablets.

Firing Line-Nov, 1971, pp. 15-16 Nitrostat: An Exciting New Product For P-D (Parke-Davis).

Fusari, J. Pharm. Sci. 62 (1): 122-129, Jan, 1973. Nitroglycerin Sublingual Tablets 1. Stability of Conventional Tablets.

Fusari, J. Pharm. Sci. 62(12): 1910-2021, Dec., 1973 Nitroglycerin Sublingual Tablets 11. Preparation and Stability of a New, Stabilized, Sublingual, Molded Nitroglycerin Tablet.

Primary Examiner-Shep K. Rose [57] ABSTRACT Methods for preparing nitroglycerin containing pharmaceutical compositions in the form of tablets suitable for Sublingual administration, are disclosed, which comprises wetting a substantially dry mixture of the nitroglycerin and a solid, water-soluble pharmaceutical carrier with a solvent mixture containing a nonvolatile, water-soluble solvent and a volatile solvent, forming the wetted mixture into tablets, and removing the volatile solvent.

2 Claims, N0 Drawings STABILIZATION OF MOLDED SUBLINGUAL NITROGLYCERIN TABLETS SUMMARY AND DETAILED DESCRIPTION This application is a continuation-in-part of my copending application Ser. No. 149,072, filed June 1, I971, now U.S. Pat. No. 3,787,ll9, dated Jan. 29, 1974.

The present invention relates to methods for producing new and improved pharmaceutical compositions of nitroglycerin.

Nitroglycerin (glyceryl trinitrate) is widely used in medical practice as a coronary vasodilator. It is normally used in the form of tablets for sublingual administration containing approximately 0.2 to 0.65 mg. of nitroglycerin per tablet. Nitroglycerin tablets are administered for the purpose of producing a rapid coronary vasodilator effect relieving acute attacks of angina pectoris. and thus it is important that they retain the correct potency in terms of the active ingredient and that the active ingredient be promptly released for absorption upon sublingual administration.

It is known that nitroglycerin tablets that meet accepted standards of potency and uniformity at the time of manufacture may fail to meet those standards of potency and uniformity following storage over a period of only a few months or less.

it has been found that the failure of nitroglycerin tablets to maintain satisfactory potency and uniformity upon storage can be attributed to a migration of nitroglycerin from tablet to tablet and from the tablets to the environment. It has been found that the migration of nitroglycerin from the tablets to the environment is especially significant when the container is not tightly sealed so that the nitroglycerin can volatilize from the tablets through the loose seal into the atmosphere. It has also been found that the migration of nitroglycerin from the tablets to the environment is especially significant when the container has rayon or cotton stuffing material whereby nitroglycerin is volatilized from the tablets and absorbed on the stuffing material. In addition, migration of nitroglycerin from tablet to tablet with resulting loss of uniformity has been found to occur even in sealed glass containers without rayon or cotton stuffing material. The lack of uniformity can be demonstrated by the fact that after storage some tablets have abnormally high potency and some tablets have abnormally low potency, even though the average potency may remain within acceptable limits.

My co-pending application discloses pharmaceutical compositions of nitroglycerin that retain an acceptable level of potency even in an imperfectly sealed container and in the presence of rayon, cotton, or other material capable of absorbing nitroglycerin.

It is an object ofthis invention to provide methods for producing said pharmaceutical compositions containing nitroglycerin that retain an acceptable level of potency even in an imperfectly sealed container and in the presence of rayon, cotton, or other material capable of absorbing nitroglycerin.

Another object of the invention is to provide methods for producing pharmaceutical formulations of nitroglycerin in the form of sublingual tablets which do not undergo a significant degree of migration of nitroglycerin from tablet to tablet within the same container.

A further object of the invention is to provide methods for producing pharmaceutical formulations of nitroglycerin in the form of sublingual tablets which retain their original potency without significant deviation over a long period of storage.

Still a further object of the invention is to provide methods for producing pharmaceutical formulations of nitroglycerin in the form of sublingual tablets having the improved potency retention mentioned above and having in addition the characteristic of giving rapid release of nitroglycerin upon sublingual administration.

These as well as other objects which will appear hereinafter are achieved by the methods for producing the new pharmaceutical compositions as described below.

The new pharmaceutical compositions of nitroglycerin which are prepared in accordance with this invention contain in finished form (a) one part by weight of nitroglycerin, in combination with (b) 0.1 to 4 parts by weight of a nonvolatile, water-soluble solvent, and (c) 20 to 200 parts by weight ofa solid, water-soluble pharmaceutical carrier. The term non-volatile is used herein in a relative sense to designate a solvent that when incorporated in the finished formulation volatilizes to no more than a minor extent over a period of several months at ordinary temperatures and under ordinary conditions of storage. That solvent can be a high boiling liquid or a high boiling, low melting solid that exhibits the required solvent characteristics under the conditions of use. In addition, the solvent should have a relatively high solubility for nitroglycerin. Some examples of such solvents are polyethylene glycols, tetramethylene glycol, pentamethylene glycol, polyvinylpyrrolidones, mono-lower alkyl ethers of diethylene glycol and acetate esters of mono-lower alkyl ethers of diethylene glycol, wherein lower alkyl represents a hydrocarbon group of from one to four carbon atoms. Of this group, the following are preferred, polyethylene glycols, tetramethylene glycol, pentamethylene glycol and polyvinylpyrrolidones. The polyvinylpyrrolidones preferably should have an average molecular weight in the range of 5,000 to 100,000, especially 15,000 to 50,000. The most preferred solvents being polyethylene glycols, tetramethylene glycol, and pentamethylene glycol and the ideal solvents appear to be the polyethylene glycols preferably having an average molecular weight in the range of 300 to 7,500, especially 300 to 4,000. A preferred ratio of ingedients is one part by weight of nitroglycerin to 0.5 to 0.9 parts by weight of the nonvolatile, water-soluble solvent. The solid, water-soluble pharmaceutical carrier is a sugar or a sugar derivative such as lactose, glucose, sucrose, mannitol, or sorbitol. The solid, water-soluble pharmaceutical carrier is used in an amount, within the proportions indicated above, to impart to the finished formulation the desired solid state under normal as well as extreme temperature conditions of storage and use. The new pharmaceutical formulations of nitroglycerin, as described above, are desirably provided as molded or compressed tablets suitable for sublingual administration and containing 0.1 to 1.0 mg., preferably 0.2 to 0.65 mg., of nitroglycerin per tablet. However, if desired, they can also be provided in other conventional pharmaceutical forms such as granules.

In accordance with the invention, pharmaceutical compositions of nitroglycerin in the form of tablets for sublingual administration are produced by the process which comprises (a) preparing a substantially dry mixture of one part by weight of nitroglycerin and 20 to 200 parts by weight of a solid, water-soluble pharmaceutical carrier, (b) wetting that substantially dry mixture with a solvent mixture containing 0.l to 4 parts by weight of a non-volatile. water-soluble solvent and a sufficient quantity of a volatile solvent to permit an even wetting of the substantially dry mixture by the solvent mixture, forming the wetted mixture into tablets. and (d) drying the tablets whereby substantially all of the volatile solvent is volatilized while substantially all of the non-volatile solvent remains unvolatilized. The term non-volatile is used herein in a relative sense to designate a solvent that when incorporated in the finished formulation volatilizes to no more than a minor extent over a period of several months at ordinary temperatures and under ordinary conditions of storage. That solvent can be a high boiling liquid or a high boiling, low melting solid that exhibits the required solvent characteristics under the conditions of use. In addition, the solvent should have a relatively high solubility for nitroglycerin. Some examples of such solvents are polyethylene glycols, tetramethylene glycol, pentamethylene glycol, polyvinylpyrrolidones, mono-lower alkyl ethers of diethylene glycol and acetate esters of mono-lower alkyl ethers of diethylene glycol, wherein lower alkyl represents a hydrocarbon group of from one to four carbon atoms. Of this group, the following are preferred, polyethylene glycols, tetramethylene glycol, pentamethylene glycol and polyvinylpyrrolidones. The polyvinylpyrrolidones preferably should have an average molecular weight in the range of 5,000 to l00,000, especially l5,000 to 50,000. The most preferred solvents being polyethylene glycols, tetramethylene glycol, and pentamethylene glycol and the polyethylene glycols preferably should have an average molecular weight in the range of 300 to 7,500, especially 300 to 4,000. A preferred ratio of ingredients is one part by weight of nitroglycerin to 0.5 to 0.9 parts by weight of the nonvolatile. water-soluble solvent. The term volatile is used herein in a relative sense to designate a solvent that readily volatilizes under the conditions normally used in drying pharmaceutical tablets. for example drying in air at room temperature for 12 to 48 hours. Such solvents most suitable have a boiling point of about 120 C. or lower, preferably 100C and a preferred solvent for this purpose is aqueous ethanol or water. The solid, watersoluble pharmaceutical car rier is a sugar or a sugar derivative such as lactose, glucose, sucrose, mannitol, dextrose, or sorbitol. The solid, water-soluble pharmaceutical carrier is used in an amount, within the proportions indicated above, to impart to the finished tablets the desired solid state under normal as well as extreme temperature conditions of storage and use. The tablets, as prepared above, are desirably constituted to contain 0.1 to 1.0 mg., preferably 0.2 to 0.65 mg. of nitroglycerin per tablet.

The pharmaceutical process can, if desired. be slightly altered to incorporate other ingredients into the compositions which are also useful in pharmaceutical compounding.

The pharmaceutical compositions prepared by the process of the invention exhibit the well-known activity of nitroglycerin in medical practice but show improved behavior on storage. For example, the sublingual tablets give a rapid coronary vasodilator effect when dissolved under the tongue. Additionally. they show improved retention of potency and uniformity when stored in either glass or plastic containers, with or with out stuffing materials, at temperatures from room temperature to 45 C., when compared with the behavior of tablets prepared similarly but without the inclusion of a non-volatile, water-soluble solvent.

The invention is illustrated by the following examples.

EXAMPLE I Ingredient Quantity Nitroglycerin mixture soluble, 6.93 kg. 10% nitroglycerin Diluent (lactose sucrose, .0 kg. 95:5) Solvent mixture containing:

Ethanol, 95% 338] ml.

Polyethylene glycol 400 520 ml.

Purified water 1302 ml.

H(OCH CH ),,OH, in which the average value ofn lies be tween 8.2 and 9.].

The nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture. With care, the siftable mixture is passed through a number mesh silk sieve. Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture, and then the remainder of the diluent are added to a blender and thoroughly mixed. While the blender is operating the solvent mixture is then added and the ingredients are again blended. The wetted mixture is then formed into tablets, each weighing approximately 34 mg. after air drying, on a tablet molding ma chine. Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22 to 26 C. and a dew point temperature of 6 to 9 C. The molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets, each weighing approximately 34 mg. and labeled to contain H1 50 grain (approximately 0.43 mg.) of nitroglycerin per tablet; the acceptable variation is an average assay of percent to l 10 percent of the indicated potency.

The tablets prepared as described above are suitable for sublingual administration and exhibit improved be havior on storage when compared with tablets prepared similarly but without the use of polyethylene glycol. They maintain acceptable standards of potency and uniformity upon prolonged storage at room temperature, at 37 C., and at 45 C. The improved behavior on storage is observed in closed containers as well as in containers that are opened periodically to simulate conditions of use.

EXAMPLE 2 lngredient Quantity Nitroglycerin mixture soluble, 10.2 kg. nitroglycerin Diluent (lactose sucrose. 40.8 kg. 95:5) Solvent mixture containing:

Ethanol, 9571 3135 ml.

Polyethylene glycol 400 765 ml. Purified water 1302 ml.

H(OCH CH ),,OH. in which the average value ofn lies between 82 and 9.1.

The nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture. With care, the siftable mixture is passed through a number 80 mesh silk sieve. Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture. and then the remainder of the diluent are added to a blender and thoroughly mixed. While the blender is operating the solvent mixture is then added and the ingredients are again blended. The wetted mixture is then formed into tablets. each weighing approximately 34 mg. after air drying, on a tablet molding machine. Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22 to 26C. and a dew point temperature of 6 to 9 C. The molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets. each weighing approximately 34 mg. and labeled to contain 1/100 grain (approximately 0.65 mg.) of nitroglycerin per tablet; the acceptable variation is an average assay of 90 percent to 110 percent of the indicated potency.

The tablets prepared as described above are suitable for sublingual administration and exhibit improved behavior on storage as described in Example 1.

The nitroglycerin mixture soluble is a product containing 10 percent nitroglycerin on ,B-lactose and the quantity used is 9 percent in excess of the calculated amount.

The diluent contains 95 percent by weight of the usual lactose of pharmacy (oz-lactose monohydrate) and 5 percent by weight of sucrose.

The polyethylene glycol 400 is a polymer of ethylene oxide and water, represented by the formula l-l(OCH CH ),,Ol-l, in which the average value of n lies between 8.2 and 9.1.

The nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture. With care, the siftable mixture is passed through a number mesh silk sieve. Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture, and then the remainder of the diluent are added to a blender and thoroughly mixed. While the blender is operating the solvent mixture is then added and the ingredients are again blended. The wetted mixture is then formed into tablets, each weighing approximately 34 mg. after air drying, on a tablet molding machine. Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22 to 26 C. and a dew point temperature of 6 to 9 C. The molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets, each weighing approximately 34 mg. and labeled to contain 1/200 grain (approximately 0.32 mg.) of nitroglycerin tablet; the acceptable variation is an average assay of to percent of the indicated potency.

The tablets prepared as described above are suitabl for sublingual administration and exhibit improved behavior on storage as described in Example 1.

According to the above procedure, upon substituting polyvinylpyrrolidone having a weight average molecular weight of 25,000 in place of the polyethylene glycol 400, in such a quantity so that the ratio of nitroglycerin to polyvinylpyrrolidone is 1:2, respectively, a stabilized product containing polyvinylpyrrolidone is obtained.

We claim:

1. In a process for the production of molded tablets capable of giving a rapid release of nitroglycerin upon sublingual administration, wherein the improvement in stability is the retaining of the original potency in each tablet during storage in sealed containers containing a plurality of such tablets and container stuffing capable of absorbing nitroglycerin, consisting of the steps a. preparing a substantially dry mixture ofone part by weight of nitroglycerin and 20 to 200 parts by weight of a solid, water-soluble pharmaceutical carrier of the class consisting of lactose, glucose,

sucrose, mannitol and sorbitol b. wetting that substantially dry mixture with a solvent mixture containing 0.5 to 0.9 parts by weight of a non-volatile, water-soluble solvent and a suffi cient quantity of a volatile solvent selected from the group consisting of polyethylene glycols having an average molecular weight of from 300 to 7,500, tetramethylene glycol, and pentamethylene glycol. 2. Process of claim 1 wherein the solid, water soluble pharmaceutical carrier is substantially a mixture of lactose and sucrose. 

1. IN A PROCESS FOR THE PRODUCTION OF MOLDED TABLETS CAPABLE OF GIVING A RAPID RELEASE OF NITROGLYCERIN UPON SUBLINGUAL ADMINISTRATION, WHEREIN THE IMPROVEMENT IN STABILITY IS THE RETAINING OF THE ORIGINAL POTENCY IN EACH TABLET DURING STORAGE IN SEALED CONTAINERS CONTAINING A PLURALITY OF SUCH TABLETS AND CONTAINER STUFFING CAPABLE OF ABSORBING NITROGLYCERIN, CONSISTING OF THE STEPS A. PREPARING A SUBSTANTIALLY DRY MIXTURE OF ONE PART BY WEIGHT OF NITROGLYCERIN AND 20 TO 200 PARTS BY WEIGHT OF A SOLID, WATER-SOLUBLE PHARMACEUTICAL CARRIER OF THE CLASS CONSISTING OF LACTOSE, GLUCOSE, SUCROSE, MANNITOL AND SORBITOL B. WETTING THAT SUBSTANTIALLY DRY MIXTURE WITH A SOLVENT MIXTURE CONTAINING 0.5 TO 0.9 PARTS BY WEIGHT OF A NONVOLATILE, WATER-SOLUBLE SOLVENT AND A SUFFICIENT QUANTITY OF A VOLATILE SOLVENT SELECTED FROM THE GROUP CONSISTING OF POLYETHYLENE GLYCOLS HAVING AN AVERAGE MOLECULAR WEIGHT OF FROM 300 TO 7,500, TETRAMETHYLENE GLYCOL, AND PENTAMETHYLENE GLYCOL.
 2. Process of claim 1 wherein the solid, water soluble pharmaceutical carrier is substantially a mixture of lactose and sucrose. 